Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000162.5(GCK):c.1020-10C>A

CA213703

36169 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 57477b6b-5d28-4cb6-b4f8-3d00bca60bc8

HGVS expressions

NM_000162.5:c.1020-10C>A

NM_000162.5(GCK):c.1020-10C>A

NC_000007.14:g.44145740G>T

CM000669.2:g.44145740G>T

NC_000007.13:g.44185339G>T

CM000669.1:g.44185339G>T

NC_000007.12:g.44151864G>T

NG_008847.1:g.48684C>A

NG_008847.2:g.57431C>A

ENST00000395796.8:c.*1018-10C>A

ENST00000616242.5:c.*140-10C>A

ENST00000683378.1:n.246-10C>A

ENST00000336642.9:c.54-10C>A

ENST00000345378.7:c.1023-10C>A

ENST00000403799.8:c.1020-10C>A

ENST00000671824.1:c.1083-10C>A

ENST00000672743.1:n.32-10C>A

ENST00000673284.1:c.1020-10C>A

ENST00000336642.8:c.72-10C>A

ENST00000345378.6:c.1023-10C>A

ENST00000395796.7:c.1017-10C>A

ENST00000403799.7:c.1020-10C>A

ENST00000437084.1:c.969-10C>A

ENST00000459642.1:n.390C>A

ENST00000473353.1:n.318-10C>A

ENST00000616242.4:c.1017-10C>A

NM_000162.3:c.1020-10C>A

NM_033507.1:c.1023-10C>A

NM_033508.1:c.1017-10C>A

NM_000162.4:c.1020-10C>A

NM_001354800.1:c.1020-10C>A

NM_001354801.1:c.9-10C>A

NM_001354802.1:c.-121-10C>A

NM_001354803.1:c.54-10C>A

NM_033507.2:c.1023-10C>A

NM_033508.2:c.1017-10C>A

NM_033507.3:c.1023-10C>A

NM_033508.3:c.1017-10C>A

NM_001354803.2:c.54-10C>A

Likely Pathogenic

PP4_Moderate PM2_Supporting PP1_Strong PP3

PS4

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1020-10C>A variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 8 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.95 for acceptor loss, predicting that the variant disrupts the acceptor site of intron 8 of GCK (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, three-generation, dominant family history of diabetes or hyperglycemia, and antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.1020-10C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP4_Moderate, PP1_Strong.

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, three-generation, dominant family history of diabetes or hyperglycemia, and antibody negative) (PP4_Moderate; internal lab contributors).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP1_Strong

This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in 2 families (PP1_Strong; internal lab contributors).

PP3

The computational splicing predictor SpliceAI gives a score of 0.95 for acceptor loss, predicting that the variant disrupts the acceptor site of intron 8 of GCK (PP3).

PS4

This variant was identified in three unrelated individuals with hyperglyemia; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributors)

Approved on: 2024-02-02

Published on: 2024-02-02

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